Abstract Future improvements in acute myeloid leukemia (AML) therapy will require treatments that more effectively eradicate leukemia, while at the same time reduce the severity of chemotherapeutic side effects such as bleeding due to thrombocytopenia. The proposed project will focus on both of these issues. One approach to improving AML chemotherapy is to identify key differences in proteins that impact the function of important transporters in AML. We propose that the vulnerability of AML to both conventional and newer targeted chemotherapy can be exploited by identifying key proteins that affect the function of the ABC transporter, ABCC4, a protein highly expressed in AML. Our preliminary data reveal that MPP1, a PDZ-binding protein that is highly expressed in AML physically interacts with ABCC4 through its PDZ-motif. Importantly, high expression of MPP1 is a poor prognostic factor in AML. A central hypothesis driving our proposal is that the protein interaction between ABCC4 and MPP1, mediated by ABCC4-PDZ motif, is crucial to the MPP1 driven hematopoietic progenitor transformation as well as ABCC4 mediated export of chemotherapeutic drugs. Our second hypothesis relates to a novel mechanism impacting platelet production. This hypothesis was based upon recent GWAS studies that identified ABCC4 as one of the novel genetic determinants of platelet formation during megakaryopoiesis (platelet formation) (2, 7). It is unknown if ABCC4 has a role in megakaryopoiesis. We propose highly integrated studies that focus on the ABCC4 transporter, a protein that is expressed megakaryocytes, the cell responsible for the genesis of platelets. (1) Using both in vitro and in vivo AML models and cell lines, we will investigate how ABCC4 and MPP1 interact to produce transformation/immortalization of hematopoietic progenitors as well as confer resistance to chemotherapeutic drugs in AML, (2) Determine the domains of MPP1 required to alter ABCC4 function, and (3) Elucidate how ABCC4 regulates the formation of platelets from megakaryocytes.